Increased incidence of obesity, hyperlipidemia, hypertension, non-insulin dependent diabetes and coronary artery disease often cluster in the same individuals, and it has been frequently asserted that a common mechanism may be responsible for the comorbidity of these conditions in a subset of the population. The risk factor constellation for this group is often referred to as the “metabolic syndrome”, “insulin resistance syndrome” or “syndrome X”. The prevalence of the metabolic syndrome is roughly 2.5% in individuals under 40 years of age, rising to 5 to 10% in middle aged and older persons (1). The reasons for this increase in risk is largely due to the corollary age-related increase in obesity, and in particular abdominal obesity in the U.S. population. Obesity is now estimated to be the second leading preventable cause of death after cigarette smoking in the U.S. (2). Thirty-nine million Americans are estimated to be obese (having a body-mass-index (BMI) of ≧30) and an additional 57 million are estimated to be overweight (BMI between 25 and 29). Abdominal obesity, which increases with age among men and postmenopausal women, is responsible for most of the association of obesity with the metabolic syndrome and associated diseases (3). In addition to insulin resistance and hypertension, the principal abnormalities associated with the metabolic syndrome in obese individuals include elevated triglyceride levels and elevated cholesterol/HDL ratio. Increases both in triglyceride and cholesterol/HDL ratio are now recognized as independent risk factors for coronary artery disease (CAD) as well as overall 5-year mortality (4). However, it has remained unclear what distinguishes those individuals whose weight gain leads to the development of the metabolic syndrome from those more fortunate persons who appear capable of considerable weight gain without experiencing the dyslipidemia and insulin resistance that trigger increased risk of developing CAD and non-insulin-dependent diabetes mellitis (NIDDM).
The acid phosphatase locus 1 (ACP1) encodes a low molecular weight protein tyrosine phosphatase (LMPTP) involved in the negative modulation of insulin signal transduction (5). The ACP1 gene product is present ubiquitously in human tissues in two isoforms, called LMPTP-A and -B (6). The same locus also encodes the adipocyte LMPTP, which also is indicated as adipocyte acid phosphatase (HAAP), and is able to dephosphorylate in vitro the tyrosine phosphorylated adipocyte lipid binding protein (ALBP) (7).
ACP1 shows genetic polymorphism corresponding to strong variations in total enzymatic activity and in the ratio between the activity of the two isoforms associated with the different genotypes (8). A positive association between those ACP1 genotypes associated with a low total enzymatic activity and extreme values of BMI in obese children and adult subjects (9, 10, 11) and in non-dyslipidemic NIDDM subjects (12) has been reported in the Italian population. In 11 Italian studies the ACP1 polymorphism has been found to be associated with clinical variability of obesity, but not with the disease itself. The ACP1 *A allele is a variation of the A allele, distinguished by a Gln to Arg substitution at position 105 of the encoded protein, and lower enzymatic activity. In a recent study by Lucarini et al., a highly significant positive association between the ACP1 *A allele (associated with a reduced total enzymatic activity) and BMI has been described, but only in those cases with blood lipid levels (BLL) in the normal range (12).